Fast-Track SBIR Grant Entitled: Protease Inhibitors for Alzheimer's The following sections marked with an asterisk (*) contain proprietary information that ALSP, Inc. requests not be released to persons outside the Government, except for purposes of review and evaluation. Abstract There currently is no drug available that stops the progression of Alzheimer's disease (AD). Neurotoxic ss-amyloid peptides (Ass) are thought to cause the disease with their accumulation in brain plaques being a hallmark. Ass are cleaved from a larger amyloid precursor protein (APP) by proteases, called [unreadable]- and [unreadable]-secretases. Compounds that inhibit [unreadable]-secretase may stop the progression of the disease by reducing the production of A[unreadable]. *Preliminary data show that the protease inhibitors, CA074Me and loxistatin, *dramatically improve the behavior and pathology in a transgenic AD mouse *model, causing a significant improvement in memory deficit, a dramatic *reduction in brain plaque, a 50% reduction in brain Ass and a similar reduction in *brain [unreadable]-secretase activity. Moreover, published data shows that these inhibitors *also reduce brain Ass and [unreadable]-secretase activity in the regulated secretory pathway *by 50-60% in the non-transgenic guinea pig model of human A[unreadable] processing. The *fact that these compounds are effective in two animal models relevant to AD drug *development strongly suggests their potential as AD therapeutics. CA074Me and loxistatin (also known as E64d or EST) are cysteine protease inhibitors and the cysteine protease, cathepsin B, is a candidate [unreadable]-secretase in the regulated secretory pathway. The inhibiton of brain [unreadable]-secretase by these compounds is likely due to inhibition of cathepsin B [unreadable]-secretase activity. Although loxistatin has been shown safe to use in humans, non-specific binding by this compound, and the structurally similar CA074Me, may limit their therapeutic use. Reversible protease inhibitors offer potential pharmacological advantages as AD therapeutics. This grant, therefore, will develop reversible, small molecule, cathepsin B inhibitors and determine their efficacy in various AD models. Published data show that the reversible peptidomimetic cathepsin B inhibitor, Ac-LVK-CHO, reduces brain A[unreadable] and brain [unreadable]-secretase activity in the guinea pig model, making it likely that the reversible cathepsin B inhibitors developed in this grant will be efficacious. If successful, the work will usher in a new class of AD therapeutics that could have a major impact on treating this dreadful disease.